This U54 Center will use translational research from brain to bedside as a tool for medication development in cocaine use disorder. Preclinical and early phase I clinical PK/PD data will provide information for go/no-go decisions on phase ll-lll clinical trials with medications that show promise for cocaine use disorder. The overall goal of this research is to create a center that can provide important preclinical and early phase I clinical data to NIDA and pharmaceutical industry partners on novel compounds for cocaine use disorder. The aims related to the theme of the center will be achieved through two cores and three projects: The Administrative Core (F. Gerard Moeller PI) serves as a general resource for the other Projects and the Educational Core, including oversight of fiscal and compliance matters, and will oversee interactions with outside entities including NIDA and the pharmaceutical industry. The Educational Core (William L. Dewey PI) will focus on training translational researchers for medication development for addictions across the two institutions. Project 1 (F. Gerard Moeller PI) is a Phase I human drug interaction study examining the safety of concurrent administration of cocaine with novel compounds, and the effects of the novel compounds on subjective response to cocaine and cocaine self-administration in non-treatment seeking CocUD subjects. The compounds to be studied will be the 5-HTac receptor agonist lorcaserin followed by the 5-HT2A receptor antagonist pimavanserin based on results of Project 3. Project 2 (Joel L. Steinberg PI) is a human neuroimaging study to determine the dose-related effects of the novel compounds (lorcaserin followed by pimavanserin) on brain function during cue reactivity tasks in abstinent CocUD subjects to provide further information on specific dosages and further evidence for go/no-go decisions on phase II clinical trials using medications as a tool to enhance relapse prevention. Project 3 (Kathryn C. Cunningham PI) is a preclinical study examining the effects of novel compounds (pimavanserin and pimavanserin plus lorcaserin) on self-administration and cue reactivity to fill in key information that is lacking on potential compounds for CocUD and will provide important information to support or refute phase I human studies.